Cripto is a 188-amino-acid cell surface protein. It was serendipitously isolated in a cDNA screen of a human embryonic carcinoma library (Ciccodicola et al., 1989, EMBO J. 8:1987-91). The Cripto protein has at least two notable domains: a cysteine-rich (cys-rich) domain, and a domain first characterized as similar to the domain found in the epidermal growth factor (EGF) family. Cripto was originally classified as a member of the EGF family (Ciccodicola et al., supra); however, subsequent analysis showed that Cripto did not bind any of the known EGF receptors and its EGF-like domain was actually divergent from the EGF family (Bianco et al., 1999, J. Biol. Chem. 274:8624-29).
The Cripto signaling pathway has remained elusive despite continued investigation. The literature supports activation of several different pathways, including a MAP kinase pathway (DeSantis et al., 1997, Cell Growth Differ. 8:1257-66; Kannan et al., 1997, J. Biol. Chem. 272:3330-35); the TGF-β pathway (Gritsman et al., 1999, Development 127:921-32; Schier et al., 2000, Nature 403:385-89); possible interactions with the Wnt pathway (Salomon et al., 2000, Endocr. Relat. Cancer. 7:199-226); and cross-talk with the EGF pathway (Bianco et al., 1999, J. Biol. Chem. 274:8624-29).
U.S. Pat. No. 5,256,643 and two patents related thereto (U.S. Pat. Nos. 5,654,140 and 5,792,616) disclose a human Cripto gene, the Cripto protein, and antibodies to Cripto.
U.S. Pat. No. 5,264,557 and three patents related thereto (U.S. Pat. Nos. 5,620,866, 5,650,285, and 5,854,399) disclose a human Cripto-related gene and protein. Also disclosed are antibodies which bind to the Cripto-related protein but do not cross react by binding to the Cripto protein itself.
Overexpression of the Cripto protein is associated with tumors in many tissues (including, but not limited to brain, breast, testicular, colon, lung, ovary, bladder, uterine, cervical, pancreatic and stomach), as demonstrated by immunostaining of human tissue with rabbit polyclonal antibodies raised against small Cripto peptides. Panico et al., 1996, Int. J. Cancer 65:51-56; Byrne et al., 1998, J. Pathology 185:108-11; De Angelis et al., 1999, Int. J. Oncology 14:437-40. The art is therefore in need of means of controlling, restricting, and/or preventing such overexpression, inhibiting Cripto activity, and inhibiting the consequences of Cripto expression (i.e., promotion and/or maintenance of cell transformation).